Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A

Abstract

Despite the fact that more than 5000 safety-related studies have been published on bisphenol A (BPA), there seems to be no resolution of the apparently deadlocked controversy as to whether exposure of the general population to BPA causes adverse effects due to its estrogenicity. Therefore, the Advisory Committee of the German Society of Toxicology reviewed the background and cutting-edge topics of this BPA controversy. The current tolerable daily intake value (TDI) of 0.05 mg/kg body weight [bw]/day, derived by the European Food Safety Authority (EFSA), is mainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studies and the derivation of the TDI have been criticized. After having carefully considered all arguments, the Committee had to conclude that the criticism was scientifically not justified; moreover, recently published additional data further support the reliability of the two- and three-generation studies demonstrating a lack of estrogen-dependent effects at and below doses on which the current TDI is based. A frequently discussed topic is whether doses below 5 mg/kg bw/day may cause adverse health effects in laboratory animals. Meanwhile, it has become clear that positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses. Particularly relevant are some recent studies with negative outcomes that addressed effects of BPA on the brain, behavior, and the prostate in rodents for extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis for human risk evaluation. Currently published conjectures that rats are insensitive to estrogens compared to humans can be refuted. Data from toxicokinetics studies show that the half-life of BPA in adult human subjects is less than 2 hours and BPA is completely recovered in urine as BPA-conjugates. Tissue deconjugation of BPA-glucuronide and -sulfate may occur. Because of the extremely low quantities, it is only of minor relevance for BPA toxicity. Biomonitoring studies have been used to estimate human BPA exposure and show that the daily intake of BPA is far below the TDI for the general population. Further topics addressed in this article include reasons why some studies on BPA are not reproducible; the relevance of oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPA exposure; increased BPA exposure by infusions in intensive care units; mechanisms of action other than estrogen receptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand, and Australia. Overall, the Committee concluded that the current TDI for BPA is adequately justified and that the available evidence indicates that BPA exposure represents no noteworthy risk to the health of the human population, including newborns and babies.

Keywords::

• Biomonitoring
• endocrine disruption
• estrogenic effects
• intensive care units
• interspecies extrapolation
• low-dose effects
• regulation
• three- and two-generation studies
• tissue deconjugation
• tolerable daily intake
• toxicokinetic modeling

Acknowledgments

We thank Prof. Wolfgang Dekant (Institute of Toxicology, University of Würzburg, Würzburg, Germany) and Prof. Regine Kahl (Institute of Toxicology, Heinrich-Heine-University, Düsseldorf, Germany) for valuable scientific discussion. The commission also thanks Ms. Susanne Lindemann for helpful bibliographic work.

Declaration of interest

Dr. H. Schweinfurth: I am an employee of Bayer Schering Pharma, which is a division of Bayer AG. The Material Sciences division of Bayer AG is one of the producers and users of BPA. In my activities as a Nonclinical Advisor I am involved in the development of drugs for my employer, although I have no responsibilities for industrial chemicals such as BPA nor a direct relationship to the latter division.

Prof. U. Gundert-Remy: In my capacity as the former head of the department responsible for human health risk assessment of chemicals at the governmental Federal Institute for Risk Assessment (BFR) in Germany, I have been involved in the EU risk assessment of bisphenol A.

Dr. W. Völkel: I am an employee of the Bavarian Health and Food Safety Authority and responsible for the realization of biomonitoring studies and assessment of toxicological research and biomonitoring studies of chemicals such as bisphenol A. I have been involved in the following studies on BPA: Human exposure to bisphenol A by biomonitoring: Methods, results and assessment of environmental exposures (W. Dekant, W. Völkel. Toxicol Appl Pharmacol 2008;228:114–134). This study was supported in part by the Polycarbonate/BPA Global Group; this review represents the individual professional views of the authors and not necessarily the views of the Polycarbonate/BPA Global Group. The studies at the University of Würzburg (Chem Res Toxicol 2002;15:1281–1287; Drug Metab Dispos 2005;33:1748–1757) were supported by the German Umweltbundesamt using equipment provided by the Deutsche Forschungsgemeinschaft and the State of Bavaria. For the studies at the Bavarian Health and Food Safety Authority (Toxicol Lett 2008;179:155–162; Environ Res 2010; in press, doi:10.1016/j.envres.2010.10.001) and for the present study no external funding was obtained.

Authors Hengstler, Foth, Gebel, Kramer, Lilienblum, and Wollin report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notes

¹The Advisory Committee of the German Society of Toxicology is elected by the members of the German Society of Toxicology and consists of representatives from academia, industry, and administration in order to guarantee a broad range of toxicological competence. The Advisory Committee may consult further experts with expertise in specific fields of Toxicology. In case of the present work, the committee included Dr. Wolfgang Völkel as an additional expert and sent the manuscript to Wolfgang Dekant, and Regine Kahl for discussion. The Advisory Committee presents and justifies its activities to the members of the German Society of Toxicology, for example at the yearly plenary meeting. The German Society of Toxicology is the largest scientific toxicological organization in Europe, with more than 1000 members.

²See, for example, the criteria on reliability, relevance, and adequacy of data and studies by Klimisch et al., 1997.